This invention relates to methods for employing diphenylhalonium ion to elicit various pharmacological effects treating different types of cardiovascular dysfunction. In accordance with the present invention, diphenylhalonium ion has been found to be useful in stimulating guanylate cyclase activity, increasing the contractility of cardiac muscle and inhibiting the aggregation of blood platelet cells, each effect being desirable in ameliorating symptoms associated with particular pathogical or pathogenic conditions.
Sodium nitroprusside (SNP), administered intravenously, is an extremely potent relaxant of vascular smooth muscle in both arterial and venous vessels. Prolonged administration of SNP can lead to symptoms of thiocyanate toxicity. Thyroid hormone insufficiency has also been reported during prolonged infusions of SNP. Nevertheless, SNP has become the drug of choice for treating hypertensive crises, and is also widely used in the acute management of cardiac failure. The potent activity in vivo of SNP has been linked to the drug's ability to stimulate guanylate cyclase in most mammalian tissues. The resulting elevation of guanosine 3',5'-cyclic phosphoric acid (cyclic guanosine monophosphate, hereinafter "cyclic GMP") levels can result, for example, in a relaxation of vascular smooth muscle and a decrease in the tendency for blood platelet cells to aggregate. See, e.g., Bohme et al, "Effects of sodium nitroprusside and other smooth muscle relaxants on cyclic GMP formation in smooth muscle and platelets," ADV. CYCLIC NUCLEOTIDE RES. 9: 131-43 (1978).
Although SNP is used to treat cardiac failure from a variety of causes, the cardiac glycosides, such as digitalis, still play a principal role in the treatment of chronic heart failure, in part because they can be taken orally, unlike SNP, which must be administered intravenously. But in addition to a comparatively narrow toxic-to-therapeutic ratio, cardiac glycosides also generally display a relatively weak inotropic effect. This deficiency in the pharmacological profile of cardiac glycosides has prompted an ongoing search for potent inotropic agents that can be employed in the management of severe congestive heart failure. See Baim et al, "Evaluation of a new bipyridine inotropic agent--Milrinone--in patients with severe congestive heart failure," NEW ENGL. J. MED. 309: 748-56 (1983).
Ideally, a single hemodynamic agent would combine SNP-like activity with inotropic activity, and would be suitable for administration by more than one route, e.g., orally as well as intravenously. Such an agent would be extremely useful in treating heart failure, since it could act to increase the force of contraction of the failing ventricle while concomitantly decreasing the total peripheral resistance against which the weakened heart must work. See Cohn and Franciosa, "Vasodilator therapy of cardiac failure," NEW ENGL. J. MED. 297: 27-31, 254-58 (1977). To the extent that the agent's SNP-like activity included elevating cGMP levels in blood platelets, the agent could also inhibit platelet aggregation, thereby ameliorating the atherosclerotic condition which is often present in patients with heart failure and to which platelet aggregation contributes.
While there is an extensive literature concerning candidates for therapeutic hemodynamic agents, there has apparently been no recognition in the art of pharmacological activity for diphenylhalonium-based compounds in this regard. One bivalent iodine compound, diphenyleneiodonium, and several of its derivatives have been identified as potent hypoglycemic agents, causing substantial, irreversible decreases of sugar levels in the blood of several animal species when administered orally in relatively low dosages. Gatley and Martin, "Some aspects of the pharmacology of diphenyleneiodonium, a bivalent iodine compound," XENOBIOTICA 9: 539-46 (1979). At the cellular level, diphenyleneiodonium catalyzes an exchange of Cl.sup.- and OH.sup.- ions across biological membranes, and, independently, diminishes the rate of respiration in mitochondria by inhibiting the oxidation of NADH-linked substrates. Id. The hypoglycemia-inducing activity of diphenyleneiodonium has been linked to the compound's ability to impair gluconeogenesis secondarily, via inhibition of mitochondrial NADH oxidation. Holland et al, "Mechanism of action of the hypoglycemic agent diphenyleneiodonium," J BIOL. CHEM. 218: 6050-59 (1973).
In addition, the oral administration of diphenyliodonium salts, such as diphenyliodonium chloride (DIC), is a proven means for selectively inhibiting microbial deamination in ruminant animals and, thereby, protecting aminated components in the animals' diet from ruminal fermentation. Chalupa, "Manipulating rumen fermentation," J. ANIMAL SCI. 46: 585-99 (1977). Chalupa et al, U.S. Pat. No. 3,862,333, specifically discloses a method for inhibiting the deamination of amino acids by rumen microbes, comprising the oral administration to a ruminant of an effective, nontoxic quantity of a diphenyliodonium salt. Broderick and Balthrop, "Chemical inhibition of amino acid deamination by ruminal microbes in vitro," J. ANIMAL SCI. 49: 1101-11 (1979), similarly conclude that DIC effectively inhibits deamination at very low ruminal concentrations, and suggest DIC's utility as a feed additive.
Thus, the above-summarized literature on the physiological effects of bivalent iodine compounds makes no mention of hemodynamic activity. In particular, disclosures in the art concerning a sodium nitroprusside-like effect by any species of diphenylhalonium ion are unknown.